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Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease

Nature Immunology volume 15, pages 767776 (2014) | Download Citation

Abstract

Regulatory T (Treg) cells suppress the development of inflammatory disease, but our knowledge of transcriptional regulators that control this function remains incomplete. Here we show that expression of Id2 and Id3 in Treg cells was required to suppress development of fatal inflammatory disease. We found that T cell antigen receptor (TCR)-driven signaling initially decreased the abundance of Id3, which led to the activation of a follicular regulatory T (TFR) cell–specific transcription signature. However, sustained lower abundance of Id2 and Id3 interfered with proper development of TFR cells. Depletion of Id2 and Id3 expression in Treg cells resulted in compromised maintenance and localization of the Treg cell population. Thus, Id2 and Id3 enforce TFR cell checkpoints and control the maintenance and homing of Treg cells.

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Acknowledgements

We thank A. Bortnick for critical reading of the manuscript, S. Kuan, B. Lin and Z. Ye for help with Illumina DNA sequencing, B. Ren for access to the Illumina Hi-Seq instrumentation, A. Goldrath (University of California San Diego) for Id2-YFP mice, Y. Zhuang for Id3fl/fl mice (Duke University), A. Lasorella (Columbia University) for Id2fl/fl mice, Y. Zheng (Salk Institute) for Foxp3-deficient organs, C. Katayama, M. Suzukawa, L. Deng, P. Rosenthal, T. Katakai, A. Beppu and A. Coddington for technical advice, J. Lee (Mayo Clinic) for providing the MBP antibodies, and members of the University of California, San Diego Histology Core for performing histology. This work was supported by US National Institutes of Health (AI 38425, AI 70535 and AI 7211 to D.H.B. and CA054198, CA78384 and 1P01AI102853 to C.M.).

Author information

Author notes

    • Masaki Miyazaki
    • , Kazuko Miyazaki
    •  & Shuwen Chen

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Biology, University of California, San Diego, La Jolla, California, USA.

    • Masaki Miyazaki
    • , Kazuko Miyazaki
    • , Shuwen Chen
    • , Li-Fan Lu
    •  & Cornelis Murre
  2. Department of Immunology and Microbiology, Meiji University of Integrative Medicine, Hiyoshi-cho, Kyoto, Japan.

    • Manami Itoi
  3. Department of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Marina Miller
    •  & David H Broide
  4. Department of Pathology, University of California, San Diego, La Jolla, California, USA.

    • Nissi Varki
  5. Center for Computational Biology, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.

    • Aaron N Chang

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Contributions

M.Miy., K.M. and S.C. performed the majority of experiments. K.M. performed RNA-seq analysis. M.I. performed immunostaining of spleen and lymph nodes. N.V. contributed to the analysis of pathology. M.Mil. contributed to the analysis of lung tissue. L.-F.L. suggested key experiments and edited the manuscript. A.N.C. analyzed RNA-seq data. M.Miy. and C.M. wrote the manuscript. D.H.B. and C.M. supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cornelis Murre.

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    Rapid development of dermatitis in mice depleted for the expression of Id2 and Id3 in Treg cells.

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DOI

https://doi.org/10.1038/ni.2928

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